Hormones:
Chemical Messengers That Work in Parts per Trillion

ormones
are exceptionally potent chemicals that operate at concentrations
so low that they can be measured only by the most sensitive
analytical methods. When considering hormones such as estradiol,
the most potent estrogen, forget parts per million or parts per
billion. The concentrations are typically parts per trillion, one
thousand times lower than parts per billion. One can begin
to imagine a quantity so infinitesimally small by thinking of a
drop of gin in a train of tank cars full of tonic. One drop in
660 tank cars would be one part in a trillion; such a train would
be six miles long.

Pushing on with her research on
hormones, Theo Colborn discovered a central piece of the puzzle in the world of
Frederick vom Saal, a biologist at the University of Missouri. Vom Saal's
exploration of how hormones help make us who we are is a fascinating scientific
adventure in its own right. In a series of experiments with mice, he showed that
small shifts in hormones before birth can matter a great deal and have
consequences that last a lifetime. His work helped highlight the hazard posed by
synthetic chemicals that can disrupt hormonal systems.

Vom Saal's investigation of the
wondrous world of hormones began in 1976 during his postdoctoral days at the
University of Texas in Austin, inspired by the behavior of the lab mice. Like
most postdoctoral biology students, vom Saal was spending the better part of his
life in the lab, where his regular chores included breeding mice. As he played
mouse matchmaker, arranging encounters between eager males and receptive
females, he became intrigued by the interplay between the animals as he moved
them from cage to cage.

In the beginning, the small, white,
pink-eyed creatures had all seemed like cookie-cutter copies of each other. But
as he watched the females scurrying about in the breeding cages, individuals
quickly emerged from the crowd. Whenever he returned a female to a group cage
holding half a dozen females, there always seemed to be one mouse who would
attack the intruder. These were mice with an attitude-tough cookies who rattled
their tails threateningly and lashed out at their mild-mannered companions.

Such a difference between the
behavior of one female and another was striking-and puzzling. The mice were all
from a single laboratory strain that had been inbred for generations. When it
came to genes, they were virtually identical.

This simple observation set the
course for vom Saal's life's work in reproductive biology. In the years that
followed, he designed dozens of experiments to probe the mystery of how two mice
with almost the same genetic blueprint could behave so differently.

The notion persists that genes are
tantamount to destiny and that one might explain everything from cancer to
homosexuality by locating the responsible genes. But in a series of scientific
papers, vom Saal demonstrated that there are other powerful forces shaping
individuals-females as well as males-before birth. Genes, it turned out, are not
the whole story. Not by a long shot.

What vom Saal saw during those long
hours observing mice in the lab contradicted

everything he
had read. According to the scientific literature of the period (which reflected
prevailing human assumptions as much as it described animal behavior),
aggression was strictly a male behavior. But if tail-rattling, chasing, and
biting among the females weren't aggression, what would one call it?

Eventually, vom Saal's colleagues
had to concede that the behavior did look like aggression, but they tended to
shrug it off as unimportant. Males were the center of the action in animal
societies according to the prevailing wisdom in the field of animal behavior, so
what females did simply didn't matter. They were just passive baby makers.

Vom Saal wasn't so sure. His
intuition told him what he was seeing was probably important as well as
interesting. His doctoral work had centered on the role played by testosterone
in development before birth, and he knew that this hormone-found at much higher
levels in males-drives aggression.

From his observations, the tough
females weren't common, but they weren't rare either. There seemed to be roughly
one aggressive female for every six mice in the colony-something he noticed
because the mice were housed six to a cage. If the mice were clones, something
besides genes had to be shaping the aggressive females. Since birth the sisters
had been raised identically, so living conditions could not explain the
differences. Could the cause be something in their prenatal environment?

That set him to thinking about how
mice are carried before birth. Their mother's womb isn't a single compartment
like the human womb, but two separate compartments or "horns" that
branch off to the left and the right at the top of the vagina or birth canal.
The baby mice are tucked in the narrow horns like peas in a pod-as many as six
on a side. This arrangement means that some of the females will develop
sandwiched between two males.

Vom Saal began calculating
probabilities. If there were twelve mice in the typical mouse litter and if the
placement of males and females in the womb was random, how many females would
end up between two males? Roughly one in six, he figured. That supported the
theory taking shape in his head. Some of the females are markedly more
aggressive, he suspected, because they had spent their prenatal life wedged
between two males. A week before birth, the testicles in a male pup begin to
secrete the male hormone testosterone, which drives his own sexual development.
The female pups might be bathed in testosterone washing over from their male
neighbors.

Maybe, vom Saal thought, the answer
to the mystery of how genetically identical females could be so different lay in
hormones -- chemical messengers that travel in the bloodstream, carrying
messages from one part of the body to another.

In the body's constant conversation
with itself, nerves are just one avenue of communication -- the one employed for
quick, discrete messages that direct a hand to move away from a hot stove. A
large part of the body's internal conversation, however, is carried on through
the bloodstream, where hormones and other chemical messengers move about on the
biological equivalent of the information superhighway, carrying signals that not
only govern sex and reproduction but also coordinate organs and tissues that
work in concert to keep the body functioning properly.

Hormones, which get their name from
the Greek word meaning "to urge on," are produced and released into
the bloodstream by a variety of organs known as endocrine glands, including the
testicles, the ovaries, the pancreas, the adrenal glands, the thyroid, the
parathyroid, and the thymus. The thyroid, for example, produces chemical
messengers that activate the body's overall metabolism, stimulating tissues to
produce more heat. In addition to eggs, a woman's ovaries release estrogens-the
female hormones that travel in the bloodstream to the uterus, where they trigger
growth of the tissue lining the womb in anticipation of a possible pregnancy.

Yet another endocrine gland, the
pituitary, which dangles on a stalk from the underside of the brain just behind
the nose, acts as a control center, telling the ovaries or the thyroid when to
send their chemical messages and how much to send. The pituitary gets its cues
from a nearby portion of the brain called the hypothalamus, a teaspoon-size
center on the bottom of the brain that constantly monitors the hormone levels in
the blood in much the way that a thermostat monitors the air temperature in a
house. If levels of a hormone get too high or too low, the hypothalamus sends a
message to the pituitary, which signals the gland that produces this hormone to
gear up, slow down, or shut off.

The messages travel back and forth
continuously. Without this cross talk and constant feedback, the human body
would be an unruly mob of some 50 trillion cells rather than an integrated
organism operating from a single script.

As scientists have delved deeper
into the nervous, immune, and endocrine systems-the body's three great
integrating networks they have encountered profound interconnections: between
the brain and the immune system, the immune system and the endocrine system, and
the endocrine system and the brain. The links sometimes seem utterly mystifying.
How, for example, could a woman suffering from multiple personality disorder
play with a cat for hours while she was one personality and suffer violent
allergic reactions to cats when she took on another?

Some important glands, organs, and
tissues sending or receiving hormonal messages in the human body.Illustration by K Brown 1995

Nobody knows the answer to this
question, but it certainly lies in this internal conversation and the constant
babble of chemical messengers. Changes in one part of this complex,
interconnected system can have dramatic and unexpected consequences elsewhere,
often where one might least expect, because everything is linked to everything
else. A brain tumor, for example, might show up as disrupted menstrual cycles
and hypersensitivity of the skin rather than as headaches.

If hormones are vital to maintain
proper functioning in adults, they are perhaps even more important in the
elaborate process of development before birth.

But how could vom Saal test his theory?

Mouse Caesarean sections.

Just before the females were ready
to give birth at the end of their nineteen-day pregnancies, vom Saal removed the
tiny babies, who were approximately an inch long and about the size of an olive.
He marked them based on their position relative to their neighbors in the womb.
In this way, he could discover where aggressive females had spent their prenatal
lives. Thus began vom Saal's exploration of what some in the field playfully
refer to as the "wombmate" effect, known formally as intrauterine
position phenomenon.

Although vom Saal is now forty-nine
and a professor at the University of Missouri, he still looks youthful enough to
be mistaken for a graduate student. In a scientific world where many seldom
venture beyond narrow specialities, vom Saal embraces the big picture,
unabashedly declaring that he is interested in "womb-to-tomb biology."
He moves easily between elegant, tightly focused studies and a larger, more
encompassing pursuit of fundamental questions: Why does this happen? What is the
evolutionary significance?

Those first studies in Austin
confirmed his theory. As the mice removed by Caesarean section matured, the
aggressive females were, as predicted, the ones who had developed between
brothers. Each intriguing finding raised new questions, leading to more studies
and, in time, observations on thousands of mice delivered by Caesarean section.
Aggression proved just the most obvious sign of profound differences between
mouse sisters that could be predicted to a remarkable degree by their position
in the womb.

At first blush, vom Saal's results
sound like a tale of the ugly sister and the pretty sister. Not only was the
ugly sister-the mouse that had developed between males-more aggressive, but vom
Saal discovered she was significantly less attractive to males than the pretty
sisters who had spent their womb time between other females. Eight times out of
ten, a male given a choice would chose to mate with the pretty sister.

What's attractive to males isn't
the female's tiny pink eyes or the curve of her tail. The social life of mice is
governed by the nose, and the attractiveness of females depends on the social
chemicals they give off, which are called pheromones. The pretty sisters smell
"sexier" to males because they produce different chemicals than their
less attractive sisters. The prenatal hormone environment leaves a permanent
imprint on each sister that is recognized by males for the rest of her life.

Behavioral and reproductive
differences in mice can be predicted to a remarkable degree by their
position, which is related to hormone exposure, in the womb.
(Adapted from vom Saal and Dhar, 1992)Illustration by K Brown 1995

The sisters also showed dramatic
differences in their reproductive cycles. Besides finding mates more readily,
the pretty sister also matured faster than her ugly sister and came into heat-a
period of sexual receptivity-more often. As a consequence, she had more
opportunities to get pregnant and was more likely overall to produce more
offspring in her lifetime than her aggressive, unattractive sister, who
experienced puberty later and came into heat less frequently.

Even more amazing, studies by other
researchers, including Mertice Clark, Peter Karpiuk and Bennett Galef of
McMaster University, and the team of John Vandenbergh and Cynthia Huggett of
North Carolina State University, have found that the wombmate effect even
influences whether a female will give birth to more males or more females when
she has pups of her own. This is mysterious indeed, since scientists up to now
believed that the mother has no role

in determining the
sex of her offspring. Based on current understanding, it is the sperm
contributed by the father that dictates whether the egg develops into a male or
female, so how a mother influences sex ratio is still unknown. However it
happens, the pretty sisters tend to have litters made up of sixty percent
females, while the ugly sisters generally give birth to litters that are roughly
sixty percent male. As Vandenbergh wrote of this transgenerational wombmate
influence: "Brothers beget nephews."

After hearing the tale of the two
sisters, one might easily conclude that it would be wise to be a pretty sister
if one had to be a mouse. They have lots of mates and babies and, judged by the
evolutionary imperative of producing offspring, seem more successful than their
ugly sisters.

Not so fast, vom Saal cautions.
When one considers how these sisters live their lives within a mouse population
that goes through boom and bust cycles, the pretty sister begins to lose her
obvious edge. Typically, a mouse population builds to a very high peak and then
it crashes. In ordinary times when the population isn't too dense, the pretty
sisters definitely have the advantage, but as conditions become overcrowded the
pretty sisters' ability to produce babies diminishes because the females respond
to scent cues in urine that inhibit reproduction.

But these overcrowded times are
precisely when the ugly sisters come into their own. Because they are relatively
immune to the inhibiting cues, they are likely to be the only ones to produce
offspring, and the ugly sisters are the only ones tough enough to protect their
babies from attack and infanticide.

Interestingly, some studies have
shown that the mother's physical condition can also alter hormone levels in the
womb and influence the offspring. Mouse mothers that experience continuous
stress through the latter part of their pregnancies give birth to females who
have all the physical and behavioral characteristics of females who develop
between males. Maternal stress seems to override the ordinary wombmate
variations and produce a litter composed solely of tough cookies.

So what's the evolutionary lesson in this tale?

In vom Saal's view, the real lesson is the value of
variability.

The acute sensitivity of developing
mammals such as mice to slight shifts in hormone levels in the womb has been
shaped by evolution. This characteristic helped insure wide variation in the
offspring, even wider variation than that produced by genetic shuffling alone.
Variation is the way mammals have hedged their bets in the face of a rapidly
shifting environment. If you don't know what the conditions will be for your
offspring, the best thing to do is produce many different kinds in the hope that
at least one of them will be suited to the emerging moment.

Vom Saal's early. investigations
into the wombmate effect focused solely on females. The decision to look at
males to see if female wombmates had any influence on them was almost an
afterthought. Though the results would round out this line of research, vom Saal
admits he frankly did not expect to find anything remarkable. It was widely
assumed that male development was driven exclusively by testosterone, so being
next to females should make little difference.

In fact, the results of his
experiments astonished him. The wombmate effect shaped the destinies of males as
well as females and in ways that no one would have

ever
predicted. In a major paper in the prestigious journal
Science in June 1980, vom
Saal and his associates laid out the case that it was exposure to the female
hormone estrogen before birth that increased a
male's sexual activity in adult life.

Inside and outside the world of
science, many have regarded the level of male sexual activity as an index of
masculinity and a product of the male hormone testosterone. Indeed, the findings
were so counterintuitive and so contrary to assumptions about the
"male" hormone testosterone and the "female" hormone
estrogen that one of his collaborators protested that they must have somehow
mixed up the samples. Vom Saal found, however, that estrogen and testosterone
each influence males-and in ways that run counter to our conventional notions of
"maleness" and "femaleness." The effect of wombmates on
males proved an even more provocative vein of research than his earlier work on
females.

If the females seem a story of the
pretty and ugly sisters, then vom Saal's findings on the males sound like a tale
of the playboy and the good father.

As adults, the playboy males, exposed to higher
levels of estrogen by their female wombmates, showed another surprising
characteristic besides their higher rates of sexual activity. It would seem
logical to assume that exposure to estrogen might make males more solicitous
toward the young, but in fact, the opposite proved true. When placed with young
mice, these males were more likely to attack and kill babies. The
high-testosterone males who had had brothers for wombmates turned out to be the
good daddies, who surprisingly showed almost as great an inclination to take
care of pups as mouse mothers.

The playboy males were standouts in
one other respect as well -- the size of their prostate, the small gland that
wraps around the urethra, through which urine is eliminated. The males exposed
to higher levels of estrogen had prostates that were fifty percent larger than
those seen in brothers who had had male wombmates. In addition, these larger
prostates are more sensitive to male hormones in adulthood because they contain
three times the number of testosterone receptors found in the prostates of
brothers with male wombmates. More receptors generally means that the gland will
grow more quickly in response to male hormones circulating in the bloodstream in
adulthood.

Although human babies don't usually
have to share the womb with siblings, their development can nevertheless be
affected by varying hormone levels, which occur in the womb for reasons
scientists don't completely understand. Medical problems such as high blood
pressure can drive up estrogen levels, for example. Or perhaps eating tofu,
alfalfa sprouts, or other foods that are high in plant estrogens during
pregnancy could boost estrogen exposure. There is also the possibility that the
mother's body fat contains synthetic chemicals that disrupt hormones.

Whatever the source, a recent study
on opposite-sex human twins showed that wombmate effects can be detected in
people as well. The study, which focused on an obscure difference in the
auditory systems of males and females that exists from birth, found that girls
who had developed with a boy twin showed a male pattern, suggesting that they,
like vom Saal's female mice, had been somewhat masculinized by the hormones
spilling over from a male wombmate.

In the midst of all these
surprises, the male wombmate studies in mice yielded only one expected result-on
male aggression. Males with male wombmates and the highest testosterone exposure
before birth were indeed the most aggressive toward other adult males, and males
with female wombmates were the least aggressive.

Scientists working in this field
are still debating how estrogen shapes the development of males and females,
particularly the development of the brain and behavior, but vom Saal believes
that estrogen is helping to masculinize males by acting to enhance some effects
of the male hormone testosterone. Together the two hormones influence the
organization ;of the developing brain to increase the level of sexual activity
the male mouse will exhibit as an adult. Vom Saal had demonstrated that, this is
a prenatal effect rather than a consequence of adult hormone levels by
castrating the mice shortly after birth and then in adulthood administering an
identical amount of male hormone to brothers with male and female wombmates.
Even with identical hormone exposure these male mice showed different levels of
sexual activity-evidence that adult hormone levels are not the cause of these
behavioral differences.

Those who hear about vom Saal's
work typically ask him, Which is the "normal" mouse: the-pretty sister
or the ugly sister? The playboy or the good father?

"They're all
normal," vom Saal says emphatically.

The question itself seems to stem
from our dualistic notion of maleness and femaleness, which sees the two sexes
as mutually exclusive categories. In fact, there are many shades of gray and
overlap between behaviors thought of as typically male or female. Seen in this
light, there is nothing abnormal about an aggressive female or a nurturing male.
In this strain of mice, whose genetic variability has been reduced by
generations of inbreeding, these individuals reflect the variability created by
the natural influence of hormones before birth. What is "normal," vom
Saal says, returning to an evolutionary theme, is not one type of individual or
another but the variability itself.

But variability is just one of the
larger lessons emerging from vom Saal's work. It has also opened a window on the
powerful role of hormones in the development of both sexes and the extreme
sensitivity of developing mammals to slight shifts in hormone levels in the
womb. The wombmate studies have also underscored that hormones permanently "organize"
or program cells, organs, the brain, and behavior before birth,in
many ways setting the individual's course for an entire lifetime.

It is important to remember that
hormones do this without altering genes or causing mutations. They control the
"expression" of genes in the genetic blueprint an individual inherits
from its parents. This relationship is similar to that between the keys on a
player piano and the prepunched music roll that runs through and determines the
tune. Though the piano can theoretically play many tunes, it will only play the
one dictated by the pattern of holes in the music roll. During development,
hormones present in the womb determine which genes will be expressed, or played,
for a lifetime as well as the frequency of their expression. Nothing has been
changed in the individual's genes, but if a particular note hasn't been punched
into the music roll during development, it will remain forever mute. Genes may
be the keyboard, but hormones present during development compose the tune.

What is astonishing about vom
Saal's wombmate studies is how little it takes to dramatically change the
tune. Hormones are exceptionally potent chemicals that operate at concentrations
so low that they can be measured only by the most sensitive analytical methods.
When considering hormones such as estradiol, the most potent estrogen, forget
parts per million or parts per billion. The concentrations are typically parts
per trillion, one thousand times lower than parts per billion. One can
begin to imagine a quantity so infinitesimally small by thinking of a drop of
gin in a train of tank cars full of tonic. One drop in 660 tank cars would be
one part in a trillion; such a train would be six miles long.

The striking lifelong differences
between a pretty sister and ugly sister stem from no more than a thirty-five
parts per trillion difference in their exposure to estradiol and a one part per
billion difference in testosterone. Using the gin and tonic analogy, the pretty
sister's cocktail had 135 drops of gin in one thousand tank cars of tonic and
the ugly sister's 100 drops-a difference that might not be detectable in a glass
much less in a tank car flotilla.

This is a degree of sensitivity
that approaches the unfathomable, a sensitivity, vom Saal says, "beyond
people's wildest imagination." If such exquisite sensitivity provides rich
opportunities for varied offspring from the same genetic stock, this same
characteristic also makes the system vulnerable to serious disruption if
something interferes with normal hormone levels-a frightening possibility that
first dawned on vom Saal when Theo Colborn called him to talk about synthetic
chemicals that could act like hormones.

To appreciate vom Saal's concern,
one must understand more about the intricate choreography of events before birth
known as sexual differentiation and the key role played by hormones in this
developmental ballet. In mice, elephants, whales, humans, and all other mammals
as well as in birds, reptiles, amphibians, and fish, the process that creates
two sexes from initially unisex embryos is guided by these chemical messengers.
They are the conductors that give the cues at the right moment as tissues and
organs make now-or-never choices about the direction of development. In this
central drama in which boys become boys and girls become girls, hormones have
the starring role.

Our understanding of what
determines whether a fertilized egg becomes a male or female is very recent.
Before the twentieth century, it was widely assumed that the sex of the baby was
determined by environmental factors such as temperature.

It was only in 1906 that two
scientists-Nettie Marie Stevens and Edmund Beecher Wilson-independently noted
that each cell in women had two X chromosomes while men always had an X and a Y,
an observation that led to the theory that the number of X chromosomes
determined sex. In the past decade, researchers have finally established that it
is a gene on the Y chromosome rather than the number of X chromosomes that
determines sex.

As most of us learned in high
school biology, the eggs produced by the mother all carry one X chromosome, and
the sperm from the father carry either an X or a Y chromosome. The sex of the
baby hangs in the balance as the sperm burst out of the starting gate and race
against each other in the reproductive marathon. If this most primordial of
athletic events were broadcast like the Boston Marathon, we might hear that
three Ys are neck-and-neck at the entrance to the cervix, but an X is making a
move on the outside in the push into the uterus. A field of 75 million sperm
have been pushing hard, sweeping their tails back and forth in steady swimming
motions, but in the biological equivalent of Heartbreak Hill, many are beginning
to flag as they enter the fallopian tube leading from the top of the uterus.
It's a tight race right to the finish line as the competitors crowd toward the
goal. At the finish line of this race, an egg awaits the victor, rather than a
crown of laurel, as it crashes through. If the Y-carrying sperm gets to the egg
first, the baby, who has XY chromosomes, will be a boy. If the first sperm to
the egg carries an X, the XX chromosome will produce a girl.

Such stories about the race between
the Xs and the Ys for the egg left many of us with the impression that the
outcome was all in the genetic instructions carried by the sperm. If the sperm
delivered a Y, bingo, it was a boy-what unfolded between conception and birth
was all more or less automatic and dictated by that genetic blueprint. In fact,
the process is much more complex. The sex-determining gene in that Y chromosome
has only a quick walk-on part in the elegant and wondrous process through which
boys become boys.

In animals such as birds and
humans, one sex is the basic model and the other is what might be described as a
custom job, since the latter requires a sequence of additional changes directed
by hormones to develop properly into the opposite sex. In birds, this basic
model happens to be male. In mammals, including humans, the opposite is the
case, and an embryo will develop into a female unless male hormones override the
program and set it off on the alternative course.

Although the sperm delivers the
genetic trigger for a male when it penetrates the egg, the developing baby does
not commit itself to one course or another for some time. Instead, it retains
the potential to be either male or female for more than six weeks, developing a
pair of unisex gonads that can become either testicles or ovaries and two
separate sets of primitive plumbing-one the precursor to the male reproductive
tract and the other the making of the fallopian tubes and uterus. These two duct
systems, known as the Wolffian and Müllerian ducts, are the only part of the
male and female reproductive systems that originate from different tissues. All
the other essential equipment -- which might seem dramatically different between
the two sexes -- develop from common tissue found in both boy and girl fetuses.
Whether this tissue becomes the penis or the clitoris, the scrotal sack that
carried the testicles or the folds of labial flesh around a woman's vagina, or
something in between depends on the hormonal cues received during a baby's
development.

The big moment for the Y chromosome
comes around the seventh week of life, when a single gene on the chromosome
directs the unisex sex glands to develop into male testicles. In doing this, the
Y chromosome throws the switch initiating the very first step in male
development, the development of the testes, and that is the beginning and end of
its role in shaping a male. From this point on, the remainder of the process of
masculinization is driven by hormone signals originating from the baby's
brand-new testicles. In adult life, the testicles produce sperm to fertilize a
woman's eggs, the male's contribution to reproduction and posterity. But the
testicles play an even more important role in a male's life before birth.
Without the right hormone cues at the right time-cues emanating from the
testicles-the baby will not develop the male body and brain that go along with
the testicles. It might not even develop the penis required to deliver the sperm
the testicles produce.

In girls, the changes that turn the
unisex glands into ovaries, the part of the female anatomy that produces eggs,
begin somewhat later, in the third to fourth month of fetal life. During this
same period, one set of ducts-the Wolffian ducts that provide the option for a
male reproductive tract-wither and disappear without any special hormone
instructions. While the development of the female body isn't as dependent on
hormone cues as the development of males, animal research suggests estrogen is
essential for proper development and normal functioning of the ovaries.

The process of laying the
groundwork for the reproductive tract is more complicated in males and is marked
by critical stages where hormones direct now-or-never decisions. Shortly after
they are formed, the testicles produce a special hormone whose function is to
trigger the disappearance of the female option -- the Müllerian ducts. To
accomplish this milestone, the hormone message must arrive at the right time,
because there is only a short period when the female ducts respond to the signal
to disappear. Then the testicles have to send another message to the Wolffian
ducts, because they are programmed to disappear automatically by the fourteenth
week unless they receive orders to the contrary.

The messenger is the predominantly
male hormone testosterone, which insures the preservation and growth of the male
Wolffian ducts. Under the influence of testosterone, these ducts form the
epididymis, vas deferens, and seminal vesicles-the sperm delivery system that
leads from the testicles to the penis.

A potent form of testosterone
guides the development of the prostate gland and external genitals, directing
the genital skin to form a penis and a scrotum that holds the testicles when
they finally descend from the abdomen late in a baby's development. A naturally
occurring defect dramatically illustrates what can happen if these messages do
not get through.

From time to time, a young patient
will show up in a gynecologist's office because the teenager still hasn't had
her first period although all the other girls in her class have passed this
milestone. Usually nothing serious is wrong.

But once in a rare while, the
physician will deliver an utterly shocking diagnosis. The patient isn't
menstruating because despite all appearances, she is not female. Although such
individuals have grown up as normal-looking girls, they have the XY chromosomes
of males and testicles in their abdomen instead of ovaries. But because a defect
makes them insensitive to testosterone, they never responded to the hormone cues
that trigger masculinization. They never developed the body and brain of a male.

The pictures in medical textbooks
of these unrealized males are fascinating, for there is nothing about their
unclothed bodies that looks the least bit odd or unusual. As hard as one
searches for a hint that a genetic male lurks inside these bodies, there is no
sign of development derailed. These genetic males look like perfectly ordinary
women with normally developed breasts, narrow shoulders, and broader hips.

These completely feminized males
are the most extreme example of what happens when something blocks the chemical
messages that guide development. If -anything interferes with the testosterone
or the enzyme that amplifies its effect, the common tissue found in boy and girl
fetuses will develop instead into a clitoris and other external female genitals.
In less extreme cases of disruption, males may have ambiguous genitals or
abnormally small penises and undescended testicles.

But sex is more than a purely
physical matter. According to physicians who treat them, these feminized males
not only look like women, they act and think of themselves as women. There is
nothing the least bit telling in their behavior to suggest that they are really
male. In most animals, the development of a properly functioning male or female
involves the brain as much as the genitals, and research such as vom Saal's
shows that hormones permanently shape some aspects of behavior before birth as
much as they sculpt the penis. If an individual is going to act like a male as
well as look like one, the brain must receive testosterone messages from the
testicles during a critical period when brain cells are making some of their
now-or-never decisions.

An individual who gets the wrong
hormone messages during this critical period of brain development may show
abnormal behavior and fail to mate even though it has the right physical
equipment. In an influential 1959 study, Charles Phoenix of the University of
Kansas found that female guinea pigs exposed to high levels of testosterone in
the womb acted like males. They would not show the classic female mating
posture, a raised posterior, known as "lordosis," as adults or respond
normally to the female hormones that stimulate sexual behavior and reproduction.

No one debates that hormones act to
give males and females different bodies and that their role in the development
of animals and humans is pretty much the same. But how hormones influence the
development of the human brain is hotly debated. Do they shape the brain and
behavior in humans as dramatically as they do in mice or rats or guinea pigs?
Are there structural differences between the brains of men and women, and is
there any evidence that the differences stem from hormone influences before
birth?

These questions are difficult to
answer. Not only is human behavior more complex than that of vom Saal's mice,
but we aren't free to give pregnant women various doses of hormones to see the
effect on the brain development of their babies.

Those who have probed the question
of whether the behavioral differences between men and women have a biological
basis or are purely cultural have found evidence of some structural differences
linked to hormones, but so far these sex-linked areas are fewer and less
pronounced than those seen in rats. Psychologists have also reported certain
general differences in the way men and women think, reporting that women have
greater verbal skills as a rule and men tend to be better at solving spatial
problems. Many also believe that the rough-and-tumble play and fighting seen to
a much greater degree in young boys than in girls stems from biology rather than
from culture or child-rearing methods.

At the same time that hormones are
guiding at least some aspects of sexual development of the unborn child, these
chemical messengers are also orchestrating the growth of the baby's nervous and
immune systems, and programming organs and tissues such as the liver, blood,
kidneys, and muscles, which function differently in men and women. Normal brain
development, for example, depends on thyroid hormones that cue and guide the
development of nerves and their migration to the right area in this immensely
complex organ.

For all these systems, normal
development depends on getting the right hormone messages in the right amount to
the right place at the right time. As this elaborate chemical ballet rushes
forward at a dizzying pace, everything hinges on timing and proper cues. If
something disrupts the cues during a critical period of development, it can have
serious lifelong consequences for the offspring.